Project Summary Nonmedical use and abuse of hallucinogens (including psilocybin and LSD) has remained stable over the past 12 years. Contrary to the model of abuse liability for typical drugs of abuse, where re-administration is driven by acute positive reinforcement and persistent negative reinforcement mechanisms, repeated self- administration of classic hallucinogens may be driven by long-term persisting positive reinforcement. This persisting positive reinforcement may be driven by alteration in neural processing of negative emotional stimuli subsequent to ingestion of a classic hallucinogen. We propose an open-label pilot study in healthy, hallucinogen-nave volunteers of the persisting effects of a high dose of the classic hallucinogen psilocybin on behavior and brain function related to emotion processing. Participants will undergo functional magnetic resonance imaging (fMRI) during completion of emotional processing tasks (including emotion recognition, emotion discrimination, and emotional conflict processing) at baseline (one day before a high-dose psilocybin session), one week post-psilocybin, and one month post-psilocybin. Participants will also complete well- established, validated self-report measures of mood and emotion, and validated abuse liability measures. Our aims are to assess the time-course of persisting effects of psilocybin on 1) emotion processing as measured by task performance, and 2) neural circuitry of emotion processing as measured by resting state and task-based fMRI. This study is a logical first step in investigating the atypical reinforcing properties of classic hallucinogens, and it will generate necessary preliminary data for a more comprehensive program of research in this area. The proposed study and subsequent program of research will make critical contributions to our understanding of the potential for abuse and the underlying mechanisms supporting abuse of classic hallucinogens, for which we currently know very little.